Surgery has been the classic treatment modality for cancer, and until somewhat recently, was the only treatment offering a potential cure for patients. Such a surgical approach perhaps has been predominant in the treatment of colorectal cancer. Worldwide, the incidence rates of this form of cancer vary widely, from 3.4 cases per 100,000 population in Nigeria to 35.8 cases per 100,000 population in Connecticut. See generally:
Cancer, Principles and Practice of Oncology, vol. 1, 4th ed. p. 931, J. B. Lippincott Co., Philadelphia, Pa. PA1 "Second-Look Surgery for Colorectal Cancer, The Second Time Around" by Martin, et al., Ann. Surg. vol. 214, no. 3, pp 321-327, September, 1991. PA1 "Manual for Staging Cancer" 4th Ed., edited by Beahrs, et al., pp 75-82, 1992, J. B. Lippincott Co., Philadelphia, Pa.
Where a surgical operation is elected for treatment, the resultant procedure is one of localizing the site of neoplastic tissue, or its biological precursor, differentiating it, and resecting it. ("Neoplastic tissue", for the present purposes, often is referred to as cancerous tissue, though malignant tumor and malignant tumor cells also are found in the terminology of the art. The term "neoplastic tissue" includes all of these as well as those biological disturbances occurring prior to tumor cell generation.)
The conventional practice of surgeons in locating and differentiating colorectal tumor has been through the senses of three-dimensional vision and touch, tissue under investigation being carefully observed for regions of tumor and palpated to locate that tumor which, for example, is not seen. Success in surgical procedure, however, requires that the surgeon locate all neoplastic tissue including the very smallest tumor. In fact, certain tumor, referred to as "occult" tumor, i.e. tumor which cannot be found by the conventional surgical procedures of sight and feel are somehow required to be located to assure success. Failure to locate and remove such occult tumor generally will result in the continued growth of cancer in the patient, a condition often referred to as "recurrent" cancer. This need to locate all neoplastic tissue has led to a variety of techniques to aid the surgeon. For example, a substantial amount of effort for aiding in the location neoplastic tissue has been through the utilization of radiolabeled antibody for detection purposes. One technique includes the scintillation scanning of patients injected with relatively high energy, e.g. .sup.131 I labeled antibodies. Such photo-scanning or scintillation scanning provides scintigrams difficult to interpret because of blood pool background radioactivity. Computer subtraction of radioactive blood pool agents and the use of two labeled antibodies (one specific for the tumor and one non-specific) have been attempted to enhance imaging. Nevertheless, such techniques have been found to provide little, if any, useful information to the surgeon, especially over and above CAT scans, magnetic resonance imaging, and like traditional techniques. Generally, these conventional imaging techniques will fail to locate occult tumor. As neoplastic tissue sites become smaller, the radionuclide concentrations will tend to be lost, from an imaging standpoint, in the background where blood pool radiation necessarily is present in the patient.
U.S. Pat. No. 4,782,840 by E. W. Martin, Jr., M.D., and M. O. Thurston, Ph.D. entitled "Method for Locating, Differentiating, and Removing Neoplasms", issued Nov. 8, 1988 (the disclosure of which is expressly incorporated herein by reference) reviews such scintillation scanning techniques and discloses a much improved method for locating, differentiating, and removing neoplasms. This procedure utilizes a radiolabeled antibody and a hand-held radiation detection probe which the surgeon may use intra-operatively in order to detect sites of radioactivity. The procedure is known as the "RIGS" system (RIGS being a trademark of Neoprobe Corporation, Columbus, Ohio) and is seen to achieve success in locating occult tumor. This is, in part, because the approach to localization recognizes that tumor detection should be delayed until the blood pool background of circulating radiolabeled antibody has had an opportunity to be cleared from the body. Fortuitously, the '840 patent discloses the ability of the radiolabeled antibody to remain bound to or associated with neoplastic tissue for extended periods of time with the radio tags still bound thereto. Moreover, even though the accretion of radioactivity at the tumor or neoplastic tissue site decreases over time, the blood pool background and surrounding tissue, relative to the tumor sites decreases at a much greater rate so that the radioactive sites can be determined utilizing a hand-held probe when it is positioned in close proximity with the tissue under investigation. Thus, the portable detection probe inherently employs the application of the approximate inverse square law of radiation propagation. Occult and otherwise unrecognizable neoplastic tissue is located because, for example, the number of rate based counts representing background radiation is very low, such that the resulting combination of background radiation plus the hint radiation emanating from neoplastic tissue will, while in and of itself remaining at a low level of count rates, will be detectable by a probe-contained radiation responsive crystal and its associated circuitry. To derive the presence or absence of such occult tumor, a microprocessor-driven complex system of analysis continuously works to statistically evaluate validated counts to aurally apprise the surgeon of the presence or absence of occult neoplastic tissue. The complex algorithm under which the noted evaluation takes place is described in U.S. Pat. No. 4,889,991 by R. C. Ramsey and M. O. Thurston, entitled "Gamma Radiation DetecTor with Enhanced Signal Treatment", issued Dec. 26, 1989 (the disclosure of which is expressly incorporated herein by reference). As is apparent, the data developed from the hand-held surgical probe must itself be accurately validated. This calls for amplification procedures which themselves are accurate and generally noise free; as well as photon event energy evaluations through the utilization of energy discriminating circuitry which is essentially free of inaccurate energy determinations with respect to asserted electrical signal pulses, the amplitudes of which correspond with photon emission energies.
Experience with the RIGS system has demonstrated its additional value in locating very hint neoplastic tissue occurring as a consequence of the commencement of metastasis. Not only is such neoplastic tissue located for resection, but also the surgeon is given a valuable aid in determining the proper staging of the patient in accordance with the extent and severity of the disease. Such staging aids in determining the appropriate post-surgical treatment for patients. Stage I and II patients are believed to be curable by surgery alone, whereas Stage III patients, i.e. patients determined to have cancer spread to the lymph nodes, are treated with some form of post-operative therapy, such as chemotherapy. Stage IV patients, i.e. patients with metastasis to other organs, are treated with a variety of methods, including post surgical therapy and/or surgical removal of tumor. Should hidden or occult neoplastic tissue not be found, residual disease is left behind and is not accounted for with respect to an evaluation of the extent of the disease.
The spread of colorectal cancer from its primary situs has been the subject of substantial study, the data from which can be more effectively used by the surgeon in conjunction with an understanding of the location of occult neoplastic tissue, i.e. a substantially improved evaluation of the extent of spread of the disease. Colorectal cancer first metastasizes to the perirectal nodes at the level of the primary tumor or immediately above it. Next, the chain accompanying the superior hemorrhoidal vessels is involved. In later stages of disease, when the hemorrhoidal lymphatics are blocked, there is lateral or downward spread. In colon carcinoma, normal lymphatic flow is through the lymphatic channels along the major arteries, with three eschilons of lymph nodes, pericolic, intermediate, and principal. If tumors lie between two major vascular pedicles, lymphatic flow may drain in either or both directions. If the central lymph nodes are blocked by tumor, lymphatic flow can become retrograde along the marginal arcades proximally and distally. The risk for lymph node metastasis increases with increasing tumor grade, as does the number of lymph nodes affected.
The liver is the primary site of hematogenous metastases, followed by the lung. Involvement of other sites in the absence of liver or lung involvement is rare.
Implantation refers to the release of tumor cells from the primary tumor and their deposition on another surface. Implantation has been reported with tumor cells shed intraluminally, from serosal surface through the peritoneum, and by surgical manipulation and resultant deposition on wound surfaces.
See generally:
Because of the high sensitivity of the RIGS system, lymph node involvement and the like may be identified at very early stages of colorectal cancer metastasis. This sensitivity may be occasioned by a form of biological amplification occurring wherein the radiolabeling system serves to identify sialomucin, a substance secreted by cells experiencing preliminary cancer based disturbances as well as cancerous cells themselves. Thus, while precursors to tumor may be located, such identification is realized only with a capability for carrying out an accurate evaluation of very hint tumor associated photon emissions as combined with relatively low background level radiation.
To achieve higher levels of success in developing background versus tumor evaluation, the supporting instrumentation should exhibit very high levels of reliability. In this regard, noise based upon electronics must be limited or controlled, and the front end energy evaluations by discriminator networks must be as accurate as possible with an avoidance of hazards that may become present in logic networks to evoke inaccurate validations of photon emissions or events.